Mitochondrial dysfunction has been linked to a number of neurodegenerative diseases, including Parkinson's Disease, Alzheimer's Disease and Amyotrophic Lateral Sclerosis, among others. However, the precise role of mitochondrial dysfunction in degeneration, relative to other cellular and molecular mechanisms, remains unclear. Importantly, however, rare genetic conditions such as Leigh Disease directly affect mitochondrial function and cause neurodegeneration in infants and children. This proposal develops a novel model of Leigh Disease in the fruit fly, and uses the powerful genetic, behavioral and histological tools available in this system to probe the specific mechanisms by which mitochondrial dysfunction causes degeneration. Several alternate mechanisms, including effects on cellular metabolism, and the excessive production of reactive oxygen species (ROS) have been proposed to link alterations in mitochondrial function to neuronal degeneration. Previous work demonstrates that mitochondrial dysfunction triggers two genetically distinct degenerative processes. One of these pathways is dependent on ROS production, and leads specifically to synapse loss, while the other pathway is ROS-independent and causes degeneration of cell body structures. This proposal addresses the following questions. Do ROS activate a degeneration-inducing signal, or act as chronic damaging agents, or both? What are the molecular targets of mitochondrial dysfunction that lead to neurodegeneration? Neurodegenerative diseases afflict many people, with Parkinson's Disease alone affecting more than 1 million Americans. At present, however, treatment options for most neurodegenerative diseases are highly limited. Animal models have provided new understanding of the basic molecular mechanisms underlying specific aspects of neurodegenerative disease, and have played important roles in identifying new drug targets. By developing a new model of mitochondrial encephalopathy in the fruit fly, this proposal will contribute significantly both to our fundamental understanding of neurodegenerative disease, and will identify new proteins that regulate disease progression. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases like Parkinson's Disease, Alzheimer's Disease and Amyotrophic lateral sclerosis afflict millions of Americans, yet existing treatments are of only limited efficacy. This proposal develops a new animal model of neurodegenerative disease, and uses genetic and molecular biological techniques to define novel mechanisms affecting disease progression. These studies will provide new targets for drug development, and will broadly inform treatment strategies.